4P58

Crystal structure of mouse comt bound to an inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.06 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.145 
  • R-Value Observed: 0.147 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

A fragment-based approach to identifying S-adenosyl-l-methionine -competitive inhibitors of catechol O-methyl transferase (COMT).

Lanier, M., Ambrus, G., Cole, D.C., Davenport, R., Ellery, J., Fosbeary, R., Jennings, A.J., Kadotani, A., Kamada, Y., Kamran, R., Matsumoto, S., Mizukami, A., Okubo, S., Okada, K., Saikatendu, K., Walsh, L., Wu, H., Hixon, M.S.

(2014) J Med Chem 57: 5459-5463

  • DOI: https://doi.org/10.1021/jm500475k
  • Primary Citation of Related Structures:  
    4P58

  • PubMed Abstract: 

    Catechol O-methyl transferase belongs to the diverse family of S-adenosyl-l-methionine transferases. It is a target involved in the treatment of Parkinson's disease. Here we present a fragment-based screening approach to discover noncatechol derived COMT inhibitors which bind at the SAM binding pocket. We describe the identification and characterization of a series of highly ligand efficient SAM competitive bisaryl fragments (LE = 0.33-0.58). We also present the first SAM-competitive small-molecule COMT co-complex crystal structure.

    • Organizational Affiliation: 

    Medicinal Chemistry, ‡Structural Biology, §Discovery Biology, ∥Analytical Chemistry, Takeda California Inc. , 10410 Science Center Drive San Diego California 92121, United States.


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Catechol O-methyltransferase212Mus musculusMutation(s): 0 
Gene Names: Comt, Comt1
EC: 2.1.1.6
UniProt & NIH Common Fund Data Resources
Find proteins for O88587 (Mus musculus)
Explore O88587 
Go to UniProtKB:  O88587
IMPC:  MGI:88470
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO88587
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2F6
Query on 2F6
Download Ideal Coordinates CCD File 
B [auth A]1',3'-dimethyl-1H,1'H-3,4'-bipyrazole
C8 H10 N4
LNJKDWJFZASOPC-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2F6 BindingDB:  4P58 Ki: min: 6.30e+4, max: 1.58e+5 (nM) from 2 assay(s)
Binding MOAD:  4P58 Kd: 6.30e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.06 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.145 
  • R-Value Observed: 0.147 
  • Space Group: I 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.584α = 90
b = 98.584β = 90
c = 115.104γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2014-06-25 
    • Deposition Author(s): Lanier, M.

Revision History  (Full details and data files)

  • Version 1.0: 2014-06-25
    Type: Initial release
  • Version 1.1: 2014-10-01
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description, Source and taxonomy, Structure summary